Tuberculosis (TB), which is estimated to affect 2 billion individuals worldwide, is predominately caused by an infection with Mycobacterium tuberculosis. The particular concern is increasing the prevalence of TB, which is becoming resistant to the available treatments. A genetic knockout of trpD gene, which encodes for anthranilate phosphoribosyltransferase (AnPRTase) was unable to cause disease, even in immune-deficient mice.1 AnPRTase plays an important role in the synthesis of essential amino acids in Mycobacterium tuberculosis. Therefore, this enzyme is a potential drug target for the treatment of TB and other infectious diseases.
Our research explores the synthesis of different substrate and potential transition state analogues in order to understand catalysis and inhibition of AnPRTase enzyme to aid novel drug design. We have managed to achieve effective inhibition of AnPRTase enzyme with a range of different substrate analogues with Ki values of 1.3-15 mM.2 However, these analogues were shown through X-ray crystal structures to bind to the substrate binding tunnel, with no observed binding to the actual catalytic site of the enzyme. Recently, we managed to solve the structure of a potential transition state inhibitor, which bound at the active site, giving us new insight into the enzyme and allowing us to develop far more specific inhibitors.
References:
(1) Cookson, T. V. M.; Evans, G. L.; Castell, A.; Baker, E. N.; Lott, J. S.; Parker, E. J. Biochemistry 2015, 54 (39), 6082–6092.
(2) Evans, G. L.; Furkert, D. P.; Abermil, N.; Kundu, P.; de Lange, K. M.; Parker, E. J.; Brimble, M. A.; Baker, E. N.; Lott, J. S. Biochim. Biophys. Acta - Proteins Proteomics 2018, 1866 (2), 264–274.